The BMP Pathway and Its Inhibitors in the Skeleton

Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the transforming growth factor-β family of ligands. BMPs exhibit widespread utility and pleiotropic, context-dependent effects, and the strength and duration of BMP pathway signaling is tightly regulated at numerous levels via mechanisms operating both inside and outside the cell. Defects in the BMP pathway or its regulation underlie multiple human diseases of different organ systems. Yet much remains to be discovered about the BMP pathway in its original context, i.e., the skeleton. In this review, we provide a comprehensive overview of the intricacies of the BMP pathway and its inhibitors in bone development, homeostasis, and disease. We frame the content of the review around major unanswered questions for which incomplete evidence is available. First, we consider the gene regulatory network downstream of BMP signaling in osteoblastogenesis. Next, we examine why some BMP ligands are more osteogenic than others and what factors limit BMP signaling during osteoblastogenesis. Then we consider whether specific BMP pathway components are required for normal skeletal development, and if the pathway exerts endogenous effects in the aging skeleton. Finally, we propose two major areas of need of future study by the field: greater resolution of the gene regulatory network downstream of BMP signaling in the skeleton, and an expanded repertoire of reagents to reliably and specifically inhibit individual BMP pathway components.

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Extracellular BMP Antagonists, Multifaceted Orchestrators in the Tumor and Its Microenvironment

International Journal of Molecular Sciences ◽

10.3390/ijms21113888 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3888

Author(s):

Sarah Ouahoud ◽

James C.H. Hardwick ◽

Lukas J.A.C. Hawinkels

Keyword(s):

Cancer Progression ◽

Bone Morphogenetic Proteins ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Bmp Signaling ◽

Biological Processes ◽

Adult Tissue ◽

Aberrant Expression ◽

Bmp Pathway ◽

Bmp Antagonists

The bone morphogenetic proteins (BMPs), a subgroup of the transforming growth factor-β (TGF-β) superfamily, are involved in multiple biological processes such as embryonic development and maintenance of adult tissue homeostasis. The importance of a functional BMP pathway is underlined by various diseases, including cancer, which can arise as a consequence of dysregulated BMP signaling. Mutations in crucial elements of this signaling pathway, such as receptors, have been reported to disrupt BMP signaling. Next to that, aberrant expression of BMP antagonists could also contribute to abrogated signaling. In this review we set out to highlight how BMP antagonists affect not only the cancer cells, but also the other cells present in the microenvironment to influence cancer progression.

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Inhibition of apelin expression by BMP signaling in endothelial cells

AJP Cell Physiology ◽

10.1152/ajpcell.00168.2012 ◽

2012 ◽

Vol 303 (11) ◽

pp. C1139-C1145 ◽

Cited By ~ 27

Author(s):

Odette Poirier ◽

Mariana Ciumas ◽

Mélanie Eyries ◽

Kevin Montagne ◽

Sophie Nadaud ◽

...

Keyword(s):

Endothelial Cells ◽

Transforming Growth Factor ◽

Vascular Diseases ◽

Transforming Growth Factor Β ◽

Inhibitory Effect ◽

Bmp Signaling ◽

Gene Encoding ◽

Major Pathway ◽

Bmp Pathway ◽

Microvascular Cells

The transforming growth factor-β/bone morphogenic protein (BMP) system is a major pathway for angiogenesis and is involved in hereditary vascular diseases. Here we report that the gene encoding the vasoactive and vascular cell growth-regulating peptide apelin is a target of the BMP pathway. We demonstrate that apelin expression is strongly downregulated by BMP in an endothelial cell line as well as in lung endothelial microvascular cells. We show that BMP signals through the BMPR2-SMAD pathway to downregulate apelin expression and that a transcriptional direct and indirect mechanism is required. The BMP-induced downregulation of apelin expression was found to be critical for hypoxia-induced growth of endothelial cells, because the growth inhibitory effect of BMP in this condition is suppressed by enforced expression of apelin. Thus, we describe an important link between a signaling pathway involved in angiogenesis and vascular diseases and a peptide regulating vascular homeostasis.

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The Role of BMP Signaling in Endothelial Heterogeneity

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.673396 ◽

2021 ◽

Vol 9 ◽

Author(s):

Orjin Han ◽

Boryeong Pak ◽

Suk-Won Jin

Keyword(s):

Bone Morphogenetic Proteins ◽

Molecular Mechanisms ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Bmp Signaling ◽

Molecular Characteristics ◽

Dependent Manner ◽

Comprehensive Overview ◽

Endothelial Heterogeneity ◽

Context Dependent

Bone morphogenetic proteins (BMPs), which compose the largest group of the transforming growth factor-β (TGF-ß) superfamily, have been implied to play a crucial role in diverse physiological processes. The most intriguing feature of BMP signaling is that it elicits heterogeneous responses from cells with equivalent identity, thus permitting highly context-dependent signaling outcomes. In endothelial cells (ECs), which are increasingly perceived as a highly heterogeneous population of cells with respect to their morphology, function, as well as molecular characteristics, BMP signaling has shown to elicit diverse and often opposite effects, illustrating the innate complexity of signaling responses. In this review, we provide a concise yet comprehensive overview of how outcomes of BMP signaling are modulated in a context-dependent manner with an emphasis on the underlying molecular mechanisms and summarize how these regulations of the BMP signaling promote endothelial heterogeneity.

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